This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/11/2484    most recent ATVBAHA.107.151100v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Munnix, I. C.A. Articles by Heemskerk, J. W.M. Search for Related Content PubMed PubMed Citation Articles by Munnix, I. C.A. Articles by Heemskerk, J. W.M.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2484.)
© 2007 American Heart Association, Inc.

Thrombosis

Segregation of Platelet Aggregatory and Procoagulant Microdomains in Thrombus Formation

Regulation by Transient Integrin Activation

Imke C.A. Munnix; Marijke J.E. Kuijpers; Jocelyn Auger; Christella M.L.G.D. Thomassen; Peter Panizzi; Marc A.M. van Zandvoort; Jan Rosing; Paul E. Bock; Steve P. Watson; Johan W.M. Heemskerk

From the Departments of Biochemistry and Biophysics (I.C.A.M., J.J.E.K., C.M.L.G.D.T., M.A.M.v.Z., J.R., P.E.B., J.W.M.H.), CARIM, Maastricht University, The Netherlands; the Centre for Cardiovascular Sciences (J.A., S.P.W.), University of Birmingham, United Kingdom; and the Department of Pathology (P.P., P.E.B.), Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Dr J.W.M. Heemskerk, Department of Biochemistry, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail jwm.heemskerk{at}bioch.unimaas.nl

Objective— Platelets play a dual role in thrombosis by forming aggregates and stimulating coagulation. We investigated the commitment of platelets to these separate functions during collagen-induced thrombus formation in vitro and in vivo.

Methods and Results— High-resolution 2-photon fluorescence microscopy revealed that in thrombus formation under flow, fibrin(ogen)-binding platelets assembled into separate aggregates, whereas distinct patches of nonaggregated platelets exposed phosphatidylserine. The latter platelet population had inactivated IIbβ3 integrins and displayed increased binding of coagulation factors. Coated platelets, expressing serotonin binding sites, were not identified as a separate population. Thrombin generation and coagulation favored the transformation to phosphatidylserine-exposing platelets with inactivated integrins and reduced adhesion. Prolonged tyrosine phosphorylation in vitro resulted in secondary downregulation of active IIbβ3.

Conclusions— These results lead to a new spatial model of thrombus formation, in which aggregated platelets ensure thrombus stability, whereas distinct patches of nonaggregated platelets effectuate procoagulant activity and generate thrombin and fibrin. Herein, the hemostatic activity of a developing thrombus is determined by the balance in formation of proaggregatory and procoagulant platelets. This balance is influenced by antiplatelet and anticoagulant medication.

The organization and integration of 2 key functions of platelets, aggregation and procoagulant activity, is investigated. During thrombus formation under flow, platelets in aggregates segregate from patches of coagulation-active platelets with low integrin activation. The inactivation of integrins in procoagulant platelets is triggered by tyrosine kinase activity.

Key Words: aggregation • coagulation • microdomains • platelets • integrin activation

This article has been cited by other articles:

				S. M. Jobe, K. M. Wilson, L. Leo, A. Raimondi, J. D. Molkentin, S. R. Lentz, and J. Di Paola Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis Blood, February 1, 2008; 111(3): 1257 - 1265. [Abstract] [Full Text] [PDF]